Guideline On The Investigation Of Drug Interactions

21 June 2012CPMP/EWP/560/95/Rev. 1 Corr. 2**Committee for Human Medicinal Products (CHMP)Guideline on the investigation of drug interactionsDiscussion in the Efficacy Working Party (EWP)June/October 1996February 1997Transmission to the CPMPMarch 1997Transmission to interested partiesMarch 1997Deadline for commentsSeptember 1997Re-submission to the EWPDecember 1997Approval by the CPMPDecember 1997Date for coming into operationJune 1998Draft Rev. 1 Agreed by the EWPApril 2010Adoption Rev. 1 by CHMP for release for consultation22 April 2010End of consultation Rev. 1 (deadline for comments)31 October 2010Agreed by Pharmacokinetics Working PartyFebruary 2012Adopted by CHMP21 June 2012Date for coming into effect1 January 2013This guideline replaces guideline CPMP/EWP/560/95.KeywordsInteraction, guideline, metabolism, inhibition, induction, transport,enzyme, transport protein, transporter, absorption, food, distribution,PBPK, herbal, SmPC* The correction concerns section 5.3.4.1 (p 26) and the corresponding decision tree no. 6 (p 61) to read “if theobserved Ki value is lower or equal to / /”; Appendix VII, Table 5 to read “See section 5.4.2”.* Decision tree 4.30 Churchill Place Canary Wharf London E14 5EU United KingdomTelephone 44 (0)20 3660 6000 Facsimile 44 (0)20 3660 5555Send a question via our website www.ema.europa.eu/contactAn agency of the European Union European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged.

Guideline on the investigation of drug interactionsTable of contentsExecutive summary . 41. Introduction . 42. Scope. 53. Legal basis and relevant guidelines . 54. Pharmacodynamic interactions. 65. Pharmacokinetic interactions . 65.1. Effects of food intake on the pharmacokinetics of the investigational drug . 75.2. Effects of other medicinal products on the pharmacokinetics of the investigational drug 85.2.1. Absorption . 85.2.2. Distribution . 95.2.3. Metabolism . 105.2.4. Active uptake and secretion in drug elimination . 125.2.5. Special populations . 145.3. Effects of the investigational drug on the pharmacokinetics of other drugs . 155.3.1. Absorption . 155.3.2. Distribution . 155.3.3. Metabolism . 155.3.4. Transport . 255.4. Design of in vivo studies . 265.4.1. Study population . 275.4.2. Probe drugs and cocktail studies . 275.4.3. Dose, formulation and time of administration . ch asstrong enzyme inhibitors) giving rise to relevant interactions, the pharmacokinetic characteristics ofthe investigational drug, and the safety of the drug at exposures higher than the target exposure inthe planned study. PBPK simulations may be of value in the DDI assessment at different stages in drugdevelopment (See section 5.5)Interactions at the level of absorption, distribution and elimination should be considered. If a markedinteraction is observed in vivo and the mechanism is not clear, further studies in vitro and in vivo arerecommended to clarify the mechanism of the interaction and to enable the prediction of furtherinteractions with the same or related mechanisms.5.2.1. AbsorptionThe investigation of absorption interactions serves to identify situations where the solubility,dissolution or absorption of a drug is altered by extrinsic factors. Studies of the effect of increasedgastrointestinal pH, complex binding, and modified intestinal active transport should be considered. Insome cases, drugs modulating gastric emptying and intestinal motility may be of importance. Whichstudies are needed for a specific medicinal product depend on the mode of administration,bioavailability of the medicinal product and the physicochemical properties of the investigational drug.Interactions at absorption level should be investigated mainly for orally administered investigationaldrugs and the text below refers to orally administered formulations. However, interactions should beconsidered also for inhaled and nasally administered products with potential for oral absorption.A. Interactions affecting solubilityIf the solubility of the drug or the dissolution of the formulation is markedly pH dependent in thephysiological pH range, the potential effect of drugs which increase gastric pH, such as proton pumpGuideline on the investigation of drug interactionsCPMP/EWP/560/95/Rev. 1 Corr. 2**Page 8/59

inhibitors, H2-receptor antagonists or antacids, should be investigated in vivo. If indicated by thephysicochemical properties of the drug, it may be necessary to investigate the potential for complexbinding in vitro and an in vivo study could be considered.B. Interactions affecting intestinal active transportInvolvement of transport proteins (transporters) in drug absorption is evaluated to enable predictionsof interactions where the absorption of the drug is altered due to inhibition or induction of theseproteins. Inhibition or absence of an intestinal uptake transporter can result in decreased systemicdrug exposure and/or lower Cmax. Inhibition of an intestinal efflux transporter may result in increasedsystemic drug exposure and/or increased Cmax either due to a primary increase in absorption and/or,secondarily, due to decreased availability of drug to intestinal drug metabolising enzymes (e.g. CYP3A).It is recommended that the involvement of transporters in drug absorption is evaluated in vitro inCaco-2 cells. To evaluate the importance of active transport for drug absorption, the permeability ofthe investigational drug should be taken into account. If the in vitro transport and permeability dataindicate that active intestinal transport may affect the bioavailability of the new drug, attempts shouldbe made to identify the transporter involved in vitro. Detailed recommendations on how to studyintestinal transporter involvement and to determine the apparent permeability constant in vitro isgiven in appendices II and III.When a candidate transporter has been identified, and interactions through inhibition are likely to beclinically relevant, an in vivo study with a strong inhibitor is recommended if known inhibitors areregistered as medicinal products in the EU. If the candidate transporter is subject to geneticpolymorphism, in vivo studies in subjects of certain genotypes giving rise to markedly alteredexpression or activity of the transporter may be useful for investigating the involvement of thetransporter in vivo and the estimation of the potential for pharmacokinetic interactions

for drug-drug interactions for all new chemical entities. A number of drugs have been withdrawn from the market as a result of drug-drug interactions that were only discovered post-marketing. The potential for drug-d